Structural plasticity enabling signal transfer over 30 A from the extracellular drug binding site of the adenosine A2A receptor (A2AAR) to the intracellular surface was characterized using NMR spectroscopy in solution. Based on Trp and Gly assignments throughout the receptor, we discovered local structural polymorphisms related to allosteric coupling between the orthosteric drug binding pocket and the intracellular signaling surface. This provides a dynamic structural basis for the function of the allosteric center Asp2.50. Modification of the allosteric center with replacement by Asn2.50 suppressed the structural polymorphisms on the signaling surface without affecting the conformation at the extracellular surface. Our observations suggest A2AAR extracellular and intracellular regions can function as two semi-independent subdomains for the Asn2.50 variant. As this allosteric center is one of the most highly conserved motifs among class A receptors, this implies a common signaling mechanism among many human GPCRs.
